Current approaches for assessing molecular endpoints in certain diseases usually require tissue and blood sampling, surgery, and in the case of experimental animals, sacrifice at different time points. Despite improvements in noninvasive imaging, more sensitive and specific imaging agents and methods are urgently needed. Imaging techniques capable of visualizing specific molecular targets and/or entire pathways would significantly enhance our ability to diagnose and assess treatment efficacy of therapeutic interventions for many different disease states. Most current imaging techniques report primarily on anatomical or physiological information (e.g., magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound). Newer modalities such as optical imaging and new molecular imaging probes have the potential to revolutionize the way disease is detected, treated, and monitored.
Molecular imaging is a new field in the imaging sciences that transcends the traditional boundaries of imaging structure or physiology and has the potential to revolutionize current research and clinical practices. The common paradigm for molecular imaging involves the use of a “molecular” probe or agent that selectively targets a particular gene, protein, receptor or a cellular function, with the absence, presence or level of the specific target being indicative of a particular disease state.
In particular, optical imaging offers several advantages that make it a powerful molecular imaging approach, both in the research and clinical settings. Specifically, optical imaging can be fast, safe, cost effective and highly sensitive. Scan times are on the order of seconds to minutes, there is no need for ionizing radiation, and the imaging systems can be relatively simple to use. In addition, optical probes can be designed as dynamic molecular imaging agents that may alter their reporting profiles in vivo to provide molecular and functional information in real time. In order to achieve maximum penetration and sensitivity in vivo, the choice for most optical imaging in biological systems is within the red and near-infrared (NIR) spectral region (600-900 nm), although other wavelengths in the visible region can also be used. In the NIR wavelength range, absorption by physiologically abundant absorbers such as hemoglobin or water is minimized.
Integrins are heterodimeric membrane receptors located on the cell surface that bind to the extracellular matrix (ECM). Upon ligand engagement outside of the cell, this class of adhesion receptors, through the single transmembrane helices of the dimeric subunits transmit, signals intracellularly, which can mediate a variety of biological consequences including cell growth, survival, differentiation, and apoptosis. Integrins regulate the cell cycle as well as cellular motility and morphology. In addition to binding to ECM, integrins also act as bridges connecting cells to other cells.
Structurally, integrins are heterodimeric proteins that comprise alpha (α) and beta (β) chain subunits. Multiple forms of each subunit type exist (eighteen possible α chains and eight possible β chains), allowing for great diversity in assembling heterodimeric integrins. Furthermore, splice variants of some subunits exist—allowing for even greater biological functionality and complexity. Integrins include ανβ1, ανβ3, ανβ5, ανβ6, ανβ8, α1β1, α2β1, α3β1, α3β6, α4β1, α4β7, α5β1, α6β4, α7β1, α8β1, α9β1, α10β1, αLβ2, αMβ2, αXβ2, αIIbβ3, and more recently discovered α subunits paring with β1. Among these integrins, the following integrins αν, α5β1, αIIbβ3 recognize the arginine-glycine-aspartic (RGD) sequence in proteins of the extracellular matrix (ECM). The alpha subunit associated integrins known as vitronectin receptors, ανβ3, ανβ5, and the fibronectin receptor α5β1 regulate tumor cell migration and adhesion through this specific tri-amino acid moiety (Albelda et al., CANCER RES. 1990, 5:6757-6764; Gladson and Cheresh, J. CLIN. INVEST. 1991, 88:1924-1932; Lafrenie et al., EUR. J. CANCER, 1994, 30: 2151-2158).
Angiogenesis is the formation of new blood vessels, which is necessary for growth and development, tissue repair and tumor growth. Integrins ανβ3, ανβ5 and the fibronectin receptor are known to play key role in angiogenesis. For example the integrin ανβ3 is highly expressed on activated endothelial cells during neovascularization, while weakly present in established blood vessels. This adhesion receptor ανβ3 may be an attractive target for detecting the growth of any new vasculature.